Engineering a Hybrid Thymus to Unravel the Tolerogenic Properties of Vascularized Composite Allotransplants
Abstract
Transplantation of hands, arms, and face -- reconstructive transplantation -- is a technically challenging but feasible strategy to restore functionality and quality of life for patients that suffered devastating injuries or aggressive diseases. The functional restoration and social re-integration this approach provides are vastly superior to any currently available prosthesis. There is a significant problem that limits its wide application though. The immune system of the patient recognizes the transplanted tissues as foreign entities and aggressively attacks them until complete destruction is achieved. This requires (similarly to recipient of organ transplants) the lifelong use of immunosuppressive drugs. Unfortunately, these drugs have debilitating side effects and cannot be used to the level they would be fully effective; this causes the loss of approximately 50% of the transplanted organs by 5-10 years post-transplantation. The ideal solution would be an approach to re-train the immune system to accept the transplanted tissues (transplant tolerance). To date, the only clinically successful avenue of transplant tolerance induction has been through regimens based on the concomitant use of bone marrow transplantation (from the same donor of the transplanted organ). Unfortunately, these regimens carry considerable risks and toxicities and rely on the treatment of patients several days (if not weeks) before tissue transplantation (conditioning). They are then not amenable to reconstructive transplantation. Luckily, rodent studies (including ours) have shown that transplanted limbs contain viable bone marrow that, with proper manipulation, could substitute for the execution of bone marrow transplantation. The goal of this exploratory proposal is to obtain proof of principle of the efficacy of a novel approach to complement and optimize the capacity of bone marrow to promote indefinite transplant acceptance. Our approach derives from the novel understanding of the properties of a population that resides in the thymus (the organ where the lymphocytes of the immune system develop) and is named thymic epithelial cells (TEC). They work in concert with dendritic cells (DC) to prevent the development of lymphocytes that react against self-tissues. It is actually DC that originate from the transplanted bone marrow (in the aforementioned regimens) that colonize the thymus of the patient and purge all the transplant-reactive lymphocytes. Unfortunately, TEC do not origin from the bone marrow, and the heavy conditioning required for a successful outcome of bone marrow transplantation is probably necessary to promote the colonization of a higher number of DC to compensate for the absence of TEC. Capitalizing on the activity of donor TEC could then be a major advantage in the regulation of alloreactivity. Our exploration of the thymic transplantation of TEC demonstrates that it is feasible and results in a significant modification of the reactivity of lymphocytes. Moreover, our and others studies on the differentiation of stem cells into TEC offer a solution to the paucity of cells that could be isolated for therapeutic use. Thus, we propose a novel alternative strategy to promote acceptance of limb transplants: the induction of a donor-recipient TEC "hybrid thymus" via intrathymic engraftment of donor-derived TEC. With this strategy, we expect to re-engineer the thymic environment and achieve lasting coexistence of donor and recipient-TEC that will complement the work of donor DC, bone marrow derived, to fully train developing lymphocytes to accept and protect the transplant. In this exploratory project, we will adopt our mouse model of hind limb allotranplantation to test the efficacy of our proposed approach. This would happen without the need for any heavy pre-conditioning of the transplant recipient -- a major advancement over currently explored regimens. This exploratory project is designed to provide the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610708
Entities
People
- Giorgio Raimondi
Organizations
- Johns Hopkins University
- United States Army